Case Presentation: A 56-year-old woman was referred for connective
tissue genetic evaluation because of lifelong diffuse joint laxity, with
fatigue and pain onset in her 40s. Medical history was notable for
premature menopause at age 32 years, and she had an unrevealing
endocrine work-up. Her physical examination was notable only for joint
laxity. The patient had one miscarriage and an adult son with no
learning problems. One of her two sisters had joint laxity and premature
menopause at age 31 years. Her brother had minor learning difficulties.
Her father had some tremor and gait disturbance in his late 70s and died
of unrelated causes at age 78. One of several paternal cousins had
premature menopause at age 25 years. Diagnostic testing revealed
heterozygosity for a Fragile X syndrome premutation (CGG repeat length
31 for the normal allele; 72 for the premutation allele).

Most physicians are aware that Fragile X syndrome is one of the
more common causes of male mental retardation but likely don't
expect to encounter it in a practice comprising primarily adults with
normal intelligence. While the classic presentation of Fragile X
syndrome has a prevalence in the range of 1/2,000 to 1/4,000 males,
milder forms and associated conditions now are recognized as occurring
much more frequently.

The inheritance of Fragile X syndrome and related disorders is
complicated. Excessive expansion of the CGG trinucleotide repeat within
the FMR1 gene on the X chromosome is the underlying genetic problem.
Normally, there are up to approximately 40-50 repeats, with only rare
symptoms occurring in the upper part of this range. More than 200
repeats cause mental retardation in all males and roughly half of
females. A slight oversimplification is that anything between
approximately 51 and 200 repeats is considered a premutation, with
increased risk for clinical manifestations. Recent studies suggest that
0.9%-1.3% of the general female population may be premutation carriers;
the prevalence of males with premutations is approximately half that.

Both males and females with premutations are at risk for developing
clinical symptoms. True mental retardation is very unlikely, but there
is increased risk for mild to moderate learning difficulties and/or
developmental delay. Other psychiatric manifestations occur in 20%-45%
of people with premutations, including autism spectrum disorder,
anxiety, depression, and attention-deficit disorder with or without
hyperactivity.

Men and women with premutations may also have some degree of
hypotonia and joint laxity, as in the woman described above. These
individuals may go through life with pain, fatigue, and mild to moderate
psychiatric problems, but with no other features to suggest the
underlying diagnosis.

Premature ovarian failure also is associated with FMR1 repeat
expansions, potentially including repeat sizes in the up per part of the
normal range. Risk estimates for premature ovarian failure range from
15% to 27% for women with 35-80 repeats, compared with 1% in the general
population. Interestingly, repeat lengths of more than 80 confer less
risk for premature ovarian failure, and there is no increased risk among
women with more than 200 repeats.

The most recently recognized complication of FMR1 premutation is
the Fragile X Tremor/Ataxia syndrome (FXTAS). This condition is
characterized by intention tremor and progressive cerebellar ataxia,
beginning as early as the late 50s or 60s, although symptoms might not
begin until much later in life. Other manifestations may include memory
loss, cognitive dysfunction, parkinsonism, peripheral neuropathy,
proximal lower extremity weakness, and autonomic dysfunction.

The overall prevalence of FXTAS among men with premutations is
estimated at 40% after age 50 years, starting as low as 17% in the 50s
and peaking at 75% beyond age 80 years. FXTAS also has been described in
women but is probably less common than in men. Many of the clinical
features of FXTAS are not that unusual as sporadic occurrences among a
geriatric population and could also be confused with adult
hydrocephalus. Thus, it is possible that this condition is widely
underdiagnosed.

Testing for FMR1 repeat expansions is widely available through most
clinical laboratories and requires only a small blood sample. Some labs
also offer testing on a saliva sample.

So why does any of this matter?

Although there is no specific treatment for FXTAS, FMR1-associated
premature ovarian failure, or the psychiatric and musculoskeletal
manifestations of Fragile X premutation, establishing the correct
diagnosis might prevent unnecessary additional testing and procedures.

Of much greater significance, however, is the ability to counsel
the patient and his or her family about the risk that a son, grandson,
or even great-grandson might be born with the full Fragile X mental
retardation syndrome. The complexity of such counseling is beyond the
scope of this article.

More information about Fragile X syndrome and related disorders (as
well as hundreds of other genetic conditions) is available at
www.genetests.org. Assistance in identifying a genetics clinic is
available at the same site, as well as at www.acmg.net and www.nsgc.org.

DR. LEVY is an assistant professor in the division of general
internal medicine and McKusick-Nathans Institute of Genetic Medicine,
Johns Hopkins University, Baltimore.

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